BACKGROUND: Teenagers and young adults frequently develop maculopapular exanthema following amoxicillin intake within infectious mononucleosis. The underlying pathomechanisms are still largely unknown. OBJECTIVES: To investigate whether amoxicillin-induced exanthema in florid infectious mononucleosis is a disease-associated phenomenon or results from specific sensitization to the drug. METHODS: Four patients with amoxicillin-induced exanthema within infectious mononucleosis were analysed in vivo by prick, intradermal and patch tests and in vitro by means of the lymphocyte transformation test (LTT) employing amoxicillin, ampicillin, benzylpenicillin and phenoxymethylpenicillin. RESULTS: Drug-specific sensitization to amoxicillin in the LTT was observed in three patients, two of whom showed a side-chain-specific sensitization to amoxicillin and ampicillin. The in vitro results were confirmed in vivo by skin tests. CONCLUSIONS: These data suggest that real sensitization to amoxicillin and ampicillin may occur within infectious mononucleosis and may be detected in vivo and in vitro by means of skin tests and the LTT.